Normal cell function relies on an ability of the ER to efficiently fold proteins. The crucial role of protein folding for cellular function is underscored by the number of diseases associated with the defective maturation of ER-generated polypeptides. An essential step in the folding of many proteins within the ER lumen is the formation of disulfide bonds between cysteine residues. Disulfide bond formation in proteins relies on a proper redox environment and oxidative folding in the ER is acutely sensitive to perturbation of the lumenal ER environment. My studies have revealed an unexpected role for the chaperone BiP (a member of the Hsp70 ATPase family) in coping with potentially detrimental redox alterations within the ER lumen. This BiP-centric cellular response to ER oxidative stress is mechanistically distinct from previously characterized ER stress responses and involves redox signaling via a conserved cysteine residue in BiP. Modification of BiP and alteration of its normal cellular function appears to be a physiological mechanism used to signal a redox imbalance within the ER and allow the ER to cope with an existing misoxidized substrate load. Research in my lab focuses on further defining this redox-signaling pathway within the ER. Mechanistic studies of the BiP-centric pathway in the ER in the lab will be complemented by more general proteomics approaches to identify new redox signaling pathways involving other ER resident proteins.

Research Description

My research interests focus on characterizing cellular pathways that sense and signal redox imbalances within the cell to alleviate oxidative stress. Specifically, research efforts in my lab focus on how the cell maintains a redox environment in the endoplasmic reticulum (ER) lumen appropriate for oxidative protein folding. We study the molecular mechanisms regulating cellular oxidative folding and stress pathways using a combination of molecular, genetic, and biochemical techniques.

Fass, D. and Sevier, C.S. 2009. The Ero1 sulfhydryl oxidase and the oxidizing potential of the endoplasmic reticulum in Oxidative Folding of Peptides and Proteins. Moroder, L. and Buchner, J. (Eds), Royal Society of Chemistry.